Florfenicol, the fluoro derivative of thiamphenicol, has the structure of Formula I.
Florfenicol is a broad-spectrum antibiotic compound possessing activity against many Gram negative, Gram positive, and thiamphenicol-resistant microorganisms. Florfenicol, chemically known as (1R,2S)-2-dichloroacetamido-3-fluoro-1-[4-(methylsulfonyl)phenyl]-1-propanol, is of interest as a veterinary product.
U.S. Pat. No. 4,235,892 (hereafter referred to as the “the '892 patent”) describes a process of converting thiamphenicol into Florfenicol and other analogs. The process disclosed in the '892 patent includes, for example, protection of the amino group of the amino-diol hydrochloride with a phthalic anhydride to produce a phthalimido-diol. This compound is then fluorinated to produce a phthalimido-fluoro alcohol. Removal of the protecting group with hydrazine hydrate to give a fluoro amine, which is then acylated with methyl dichloroacetate to obtain Florfenicol.
A major drawback to the process disclosed in the '892 patent is poor fluorination resulting in low production of Florfenicol and low purity. The fluorination step taught by the '892 patent is accomplished with diethylamine sulfurtrifluoride (DAST), which is expensive and hazardous to use and results in a mixture of fluorinated products. As a result, the process disclosed in the '892 patent requires further processing using of column chromatography to obtain sufficiently pure product.
An alternate approach to the fluorination step of the '892 patent is described in U.S. Pat. No. 4,876,352 (hereafter referred to as the “the '352 patent”). The '352 patent discloses the preparation of various fluoro oxazoline and oxazolidinone intermediates. The process starts from an oxazoline or oxazolidinone compound, for example, (4R,5R)-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-2-phenyl-2-oxazoline of Formula II.
The oxazoline intermediate used in the '352 patent can be prepared by simultaneously protecting the secondary hydroxyl group and the primary amino group present in (1R,2R)-2-amino-1-[(4-methylsulfonyl)phenyl]-1,3-propanediol of Formula III as described in U.S. Pat. No. 5,227,494.
This preparation requires use of toxic benzonitrile and harsh reaction conditions, such as, 18 hours of heating to 115° C. Alternatively, the desired oxazoline can be prepared as disclosed in U.S. Pat. No. 4,743,700 using ethyl benzimidate hydrochloride. The yield of the desired oxazoline product obtained using this process is low, however, with much of the remainder being isomeric oxazoline of Formula IV.

The oxazoline compounds (such as Formula II) can be converted, according to the '352 patent, to the corresponding fluoro oxazoline of Formula V, for example, by reacting with an Ishikawa reagent, (1,1,2,3,3,3-hexafluoropropyl)diethylamine under pressure.

U.S. Pat. No. 5,567,844 discloses that after performance of fluorination step, such as disclosed in the '352 patent, the fluoro oxazoline intermediates can then be hydrolyzed to obtain an amine of Formula VI.
This removal of the oxazoline protecting group requires heating at 100° C. for 18 hours with 12N hydrochloric acid and results in significant amount of by-product, the 1,3-propanediol of Formula III.
The inventors have now surprisingly found a new process of preparing Florfenicol, and analogs thereof, utilizing N-acetylated oxazolidine intermediates, which results in greater efficiency of the hydrolysis of N-acetyl oxazolidine than the prior art processes and higher product purity.